The ability of cells to normally proliferate, migrate and differentiate to various cell types is critical in embryogenesis and in the function of mature cells, including but not limited to the cells of hematopoietic and/or cardiovascular systems in a variety of inherited or acquired diseases. This functional ability of stem cells and/or more differentiated specialized cell types is altered in various pathological conditions, but can be normalized upon intracellular introduction of biologically active components. For example, abnormal cellular functions such as impaired survival and/or differentiation of bone marrow stem/progenitor cells into neutrophils are observed in patients with cyclic or severe congenital neutropenia who may suffer from severe life-threatening infections and may evolve to develop acute myelogenous leukemia or other malignancies [Aprikyan et al., Impaired survival of bone marrow hematopoietic progenitor cells in cyclic neutropenia. Blood, 97, 147 (2001); Goran Carlsson et al., Kostmann syndrome: severe congenital neutropenia associated with defective expression of Bcl-2, constitutive mitochondrial release of cytochrome C, and excessive apoptosis of myeloid progenitor cells. Blood, 103, 3355 (2004)]. Inherited or acquired disorders such as severe congenital neutropenia or Barth syndrome are triggered by various gene mutations and are due to deficient production and function of patients' blood and/or cardiac cells leading to subsequent neutropenia, cardiomyopathy and/or heart failure [Makaryan et al., The cellular and molecular mechanisms for neutropenia in Barth syndrome. Eur J Haematol. 88:195-209 (2012)]. Severe congenital neutropenia disease phenotype can be caused by different substitution, deletion, insertion or truncation mutations in the neutrophil elastase gene, HAX1 gene, or Wiskott-Aldrich Syndrome Protein gene [Dale et al., Mutations in the gene encoding neutrophil elastase in congenital and cyclic neutropenia. Blood. 96:2317-2322 (2000); Devriendt et al., Constitutively activating mutation in WASP causes X-linked severe congenital neutropenia. Nat Genet. 27:313-7 (2001); Klein et al., HAX1 deficiency causes autosomal recessive severe congenital neutropenia (Kostmann disease) Nat Genet. 39:86-92 (2007)].
Other inherited diseases like Barth syndrome, a multi-system stem cell disorder induced by presumably loss-of-function mutations in the mitochondrial TAZ gene is associated with neutropenia (reduced levels of blood neutrophils) that may cause recurring severe and sometimes life-threatening fatal infections and/or cardiomyopathy that may lead to heart failure that could be resolved by heart transplantation. In most of the cases, the mutant gene products, implicated in pathogenesis and development of inherited or acquired human diseases, affect distinct intracellular events, which lead to abnormal cellular functions and the specific disease phenotype.
Treatment of these patients with granulocyte colony-stimulating factor (G-CSF) induces conformational changes in the G-CSF receptor molecule located on the cell surface, which subsequently triggers a chain of intracellular events that eventually restores the production of neutrophils to near normal level and improves the quality of life of the patients [Welte and Dale. Pathophysiology and treatment of severe chronic neutropenia. Ann. Hematol. 72, 158 (1996)]. Nevertheless, patients treated with G-CSF may evolve to develop leukemia [Aprikyan et al., Cellular and molecular abnormalities in severe congenital neutropenia predisposing to leukemia. Exp Hematol. 31, 372 (2003); Philip Rosenberg et al., Neutrophil elastase mutations and risk of leukaemia in severe congenital neutropenia. Br J Haematol. 140, 210 (2008); Peter Newburger et al., Cyclic Neutropenia and Severe Congenital Neutropenia in Patients with a Shared ELANE Mutation and Paternal Haplotype: Evidence for Phenotype Determination by Modifying Genes. Pediatr. Blood Cancer, 55, 314 (2010)], which is why novel alternative approaches are being explored.
The intracellular events can be more effectively affected and regulated upon intracellular delivery of different biologically active molecules using distinctly functionalized nanoparticles. These bioactive molecules may normalize the cellular function or may eliminate the unwanted cells when needed. However, the cellular membrane serves as an active barrier preserving the cascade of intracellular events from being affected by exogenous stimuli.
Accordingly, there is a need in the art for new types of bioactive molecules that are capable of penetrating cellular membranes and effectuating the intracellular events of interest. The present invention fulfills these needs and provides for further related advantages.